| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
HER2-positive Advanced Solid Tumors in Phase 1.
HER2+ breast cancer and subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma in Phase 2a. |
Tumores sólidos avanzados HER2+ en Fase 1.
Cáncer de mama HER2+ y sujetos con adenocarcinoma gástrico o de la unión gastroesofágica metastásico HER2+ en la fase 2a. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Solid Tumors |
| Tumores sólidos avanzados. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066896 |
| E.1.2 | Term | HER2 positive gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084871 |
| E.1.2 | Term | Gastroesophageal junction cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the safety and tolerability profile of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors.
- Phase 1: To identify DLTs, determine the MTD or maximum administered dose of BI-1607, and propose a recommended Phase 2 dose (RP2D) for evaluation of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors |
Evaluar el perfil de seguridad y de tolerabilidad de BI-1607 en combinación con trastuzumab en sujetos con tumores sólidos avanzados HER2+.
Fase I: identificar toxicidades limitantes de la dosis (TLD), determinar la dosis máxima tolerada (DMT) o la dosis máxima administrada de BI-1607, y proponer una dosis recomendada para la fase II (DRFII) para la evaluación de BI-1607 en combinación con trastuzumab en sujetos con tumores sólidos avanzados HER2+ |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the PK profile of BI-1607 when administered every 3 weeks in combination with trastuzumab in subjects with HER2+ advanced solid tumors.
- To assess the immunogenicity of BI-1607 when administered in combination with trastuzumab.
- To assess the CD32b receptor occupancy (RO) of BI-1607 on B cells when administered in combination with trastuzumab.
- To assess possible antitumor activity of BI-1607 in combination with trastuzumab. |
Evaluar el perfil farmacocinético (FC) de BI-1607 al administrarse cada 3 semanas en combinación con trastuzumab en sujetos con tumores sólidos avanzados HER2+.
Evaluar la inmunogenia de BI-1607 al administrarse en combinación con trastuzumab.
Evaluar la ocupación del receptor (OR) CD32b de BI-1607 en linfocitos B al administrarse en combinación con trastuzumab.
Evaluar la posible actividad antineoplásica de BI-1607 en combinación con trastuzumab. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Genetic assessment (DNA analysis) |
| Evaluación genética (Análisis de ADN) |
|
| E.3 | Principal inclusion criteria |
Phase 1 and Phase 2a:
1. Is willing and able to provide written informed consent for the trial;
2. Is ≥18 years of age on day of signing informed consent;
3. Can attend the clinical site for administration of the experimental treatment;
4. Has received standard of care or is intolerant to standard of care antineoplastic therapy. Subjects who are intolerant to trastuzumab cannot be enrolled in the study;
5. Has at least 1 measurable disease lesion as defined by RECIST 1.1 criteria;
6. Has a locally confirmed HER2+ tumor (according to 2018 ASCO/CAP HER2 test guideline) by an accurate and validated assay (according to Herceptin SmPC/PI). This can be from the most recent archival tissue sample or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue obtained for the biopsy must not have been previously irradiated. Subjects who do not have an archival or new tissue sample at Screening may still be enrolled in the study provided HER2 positivity can be established.
7. Must have progressive disease after the last line of treatment. In addition, subjects must have received the following previous lines of treatment:
a. Prior lines of treatment including trastuzumab and chemotherapy.
b. At least one prior line of treatment with an antibody-drug conjugate (ADC)
8. Has left ventricular ejection fraction ≥50%.;
9. Has a life expectancy of ≥12 weeks;
10.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
11. Has adequate organ function confirmed by laboratory values.
Phase 2a Only:
12. Cohort 1 (HER2+ locally advanced or metastatic breast cancer):
a. Has histologically confirmed breast adenocarcinoma that is un-resectable loco-regional, or metastatic.
b. Must have received a minimum of 1 and a maximum of 3 prior anti–HER2-based regimens with documented progression on the most recent regimen.
13. Cohort 2 (HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma):
a. Has histologically confirmed metastatic gastric or gastroesophageal adenocarcinoma.
b. Must have received a minimum of 1 and a maximum of 2 prior anti–HER2-based regimens with documented progression on the most recent regimen. |
Fase I y fase IIa
1. Querer y poder dar su consentimiento informado por escrito para el ensayo.
2. Tener ≥ 18 años el día de la firma del consentimiento informado.
3. Poder asistir al centro clínico para la administración del tratamiento experimental.
4. Haber recibido tratamiento de referencia o ser intolerante al tratamiento antineoplásico de referencia. Los sujetos que sean intolerantes al trastuzumab no pueden participar en el estudio.
5. Tener al menos 1 lesión por la enfermedad mensurable, tal como se define en los criterios RECIST v. 1.1.
6. Tener un tumor HER2+ confirmado a nivel local (según las directrices de análisis del HER2 de la ASCO/CAP de 2018) mediante una evaluación precisa y validada (conforme al RCP/prospecto de Herceptin). Esto puede ser de la muestra de tejido de archivo más reciente o de material de tejido nuevo de una biopsia quirúrgica o diagnóstica obtenida recientemente. El tejido obtenido de la biopsia no debe haber recibido radiación con anterioridad. Los sujetos que no dispongan de una muestra de tejido de archivo o nueva en la selección podrán incluirse en el estudio igualmente siempre que se demuestre la positividad del HER2.
7. Presentar progresión de la enfermedad después de la última línea de tratamiento. Además, los sujetos deben haber recibido las siguientes líneas de tratamiento con anterioridad:
a. Líneas de tratamiento anteriores, incluidos el trastuzumab y quimioterapia
b. Al menos una línea de tratamiento anterior con un conjugado anticuerpo-fármaco (CAF) (p. ej., trastuzumab emtansina [TDM-1] o trastuzumab deruxtecán)
8. Presentar una fracción de eyección ventricular izquierda ≥ 50 %.
9. Tener una esperanza de vida ≥ 12 semanas.
10. Presentar un estado funcional según el Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0 o 1.
11. Tener una función adecuada de los órganos, confirmada por valores analíticos.
Solo la fase IIa
Además, para que un sujeto se incluya en la fase IIa, son necesarios los siguientes requisitos:
12. Cohorte 1 (cáncer de mama HER2+ localmente avanzado o metastásico):
a. Tener adenocarcinoma de mama confirmado histológicamente que sea locorregional no extirpable o metastásico.
b. Haber recibido como mínimo 1 y como máximo 3 tratamientos anti-HER2 para la enfermedad avanzada con progresión documentada en el tratamiento más reciente.
13. Cohorte 2 (adenocarcinoma gástrico o de la unión gastroesofágica metastásico HER2+):
a. Tener adenocarcinoma gástrico o de la unión gastroesofágica metastásico confirmado histológicamente.
b. Haber recibido como mínimo 1 y como máximo 2 tratamientos anti-HER2 con progresión documentada en el tratamiento más reciente. |
|
| E.4 | Principal exclusion criteria |
1. Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication;
2. Has known active CNS metastases and/or carcinomatous meningitis;
3. Has known or suspected hypersensitivity or contraindication to trastuzumab, BI-1607, or any of their excipients. Previous isolated IRRs are not to be considered a reason for exclusion unless Grade 4 in intensity;
4. Has cardiac or renal amyloid light-chain amyloidosis;
5. Has received the following:
a. Chemotherapy or small molecule products within 2 weeks of first dose of BI- 1607.
b. Radiotherapy within 2 weeks of first dose of BI-1607.
c. Immunotherapy or biological therapy within 4 weeks before the first dose of BI-1607.
6. Has not recovered from AEs to at least Grade 1 by NCI CTCAE v5.0 due to prior anticancer therapies;
7. Has had clinically significant lung disease requiring systemic corticosteroid treatment within the last 6 months of enrollment (eg, interstitial pneumonia, pneumonitis due to other causes other than radiation, and pulmonary fibrosis) or who are suspected to have these diseases by imaging at screening period or severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy;
8. Has an active, known or suspected autoimmune disease;
9. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after last dose of BI-1607 are considered eligible;
10. Is a male subject with partner(s) of childbearing potential (unless he agrees to use a barrier method of contraception [condom plus spermicidal gel] with the female partner(s) who is using one highly effective method of contraception during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the fetus or neonate. All males should refrain from sperm donation for 12 months after last dose of study drug;
11. Has had major surgery from which the subject has not yet recovered;
12. Is at high medical risk because of nonmalignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals;
13. Has presence of chronic graft versus host disease;
14. Has had an allogenic tissue/solid organ transplant;
15. Has evidence of chronic active hepatitis B virus (HBV) infection (not including subjects with prior hepatitis B vaccination or positive serum hepatitis B surface antibody) or chronic active hepatitis C virus (HCV) infection or known history of HIV. Subjects with a history of chronic HCV whose viral load has become negative with adequate medical treatment can be enrolled;
16. Has received a live vaccine within 30 days before the first dose of study treatment;
17. Has uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
a. Myocardial infarction or stroke/transient ischemic attack within the past 6 months.
b. Uncontrolled angina within the past 3 months.
c. Any history of clinically significant arrhythmias.
d. QT interval prolongation >480 msec.
e. History of other significant heart disease.
18. Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the study;
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
20. Is participating or planning to participate in another interventional clinical trial, or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks before first dose of study drug. Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participation in an observational trial is acceptable.
21. Has a known additional malignancy of another type, except for adequately treated cone-biopsied carcinoma in situ (eg, breast carcinoma, cervical cancer in situ), adequately controlled superficial bladder cancer and basal or squamous cell carcinoma of the skin.
22. Has a diagnosis of primary or acquired immunodeficiency disorder or is taking any other form of immunosuppressive therapy within 7 days before the first dose of study drug. |
1.Dosis de prednisolona > 10mg/día (o dosis equipotentes de otros corticoesteroides) durante el ensayo que no sean como premedicación. 2.Metástasis en el SNC activas conocidas o meningitis carcinomatosa. 3.Tener hipersensibilidad conocida o presunta, o contraindicación a trastuzumab, BI-1607 o a cualquiera de sus excipientes. Las reacciones relacionadas con la infusión (RRI) anteriores y aisladas no deben considerarse un motivo de exclusión, salvo que la intensidad fuese de grado 4.
4.Padecer amiloidosis de cadena ligera amiloide cardíaca o renal. 5.Haber recibido Quimioterapia o sustancias de molécula pequeña en las 2 semanas anteriores a la primera dosis de BI 1607;Radioterapia en las 2 semanas anteriores a la primera dosis de BI-1607;Inmunoterapia o tratamiento biológico en las 4 semanas anteriores a la primera dosis de BI-1607. 6.No haberse recuperado de AA hasta lograr al menos el grado 1 según los CTCAE v 5.0 del NCI por trat. antineoplásicos anteriores. 7.Haber presentado una enfermedad pulmonar clínicamente significativa que requiriese tratamiento con corticoesteroides sistémicos en los últimos 6 meses de la inclusión o tener sospecha de presentar estas enfermedades mediante pruebas de diagnóstico por imagen realizadas en el periodo de selección o disnea grave en reposo debido a complicaciones de la neoplasia maligna avanzada, o necesitar tratamiento con oxígeno complementario. 8.Tener enfermedad autoinmunitaria activa, conocida o presunta. 9.Ser mujer y ser fértil (o estar ya embarazada o en periodo de lactancia).Se considerarán aptas las mujeres que presenten resultado negativo en la prueba de embarazo en suero u orina antes de la inclusión y acepten utilizar un método anticonceptivo de alta eficacia durante 4 semanas antes de empezar el ensayo, durante el ensayo y durante 12 meses después de la última dosis de BI-1607. 10.Ser hombre con pareja fértil (a menos que acepte utilizar un método anticonceptivo de barrera [preservativo más gel espermicida] con la pareja femenina que está utilizando un método anticonceptivo de alta eficacia durante el ensayo y durante al menos 12 meses después de completar el tratamiento).Aconsejar a los hombres con pareja embarazada o en periodo de lactancia que utilicen un método anticonceptivo de barrera (preservativo más gel espermicida) para evitar la exposición al feto o recién nacido. Todos los hombres abstenerse de donar esperma durante 12 meses después de la última dosis del medicamento del estudio. 11.Haberse sometido a cirugía mayor de la cual el sujeto no se ha recuperado aún. 12.Estar en elevado riesgo médico por enfermedad sistémica no maligna, incluidas las infecciones activas graves en tratamiento con antibióticos, antifúngicos o antivíricos. 13.Tener enfermedad injerto contra huésped crónica. 14.Haber recibido un alotrasplante de tejido/órgano sólido. 15.Tener signos de infección por VHB activa crónica (sin incluir a sujetos vacunados contra la hepatitis B previamente o con resultado positivo para el anticuerpo contra el antígeno de superficie de la hepatitis B en suero) o infección por VHC activa crónica o antecedentes conocidos de VIH.Pueden incluirse los sujetos con antecedentes de VHC crónica cuya carga viral dé negativo con el adecuado tratamiento médico. 16.Haber recibido una vacuna elaborada con microbios vivos en los 30 días anteriores a la primera dosis del tratamiento del estudio. 17.Tener enfermedad cardiovascular no controlada o significativa (consultar lista de ejemplos en el protocolo). 18.Tener trastorno psiquiátrico o de abuso de sustancias conocido que pudiera interferir con la capacidad del sujeto para cooperar con los requisitos del estudio. 19.Antecedentes o signos actuales de afecciones, tratamientos o anomalías analíticas que pudieran dificultar la interpretación de los resultados del estudio u obstaculizar la participación del sujeto a lo largo de todo el estudio, o que, a juicio del investigador responsable del tratamiento, hagan que participar en el estudio no sea la opción que más le conviene al sujeto. 20.Estar participando o tener previsto participar en otro ensayo clínico de intervención, haber participado en un ensayo con un fármaco en investigación o haber utilizado un dispositivo en investigación en los 4 meses anteriores a la primera dosis del medicamento del estudio. Los sujetos que hayan pasado a la fase de seguimiento de un estudio de investigación podrán participar siempre que hayan transcurrido 4 semanas desde la última dosis del medicamento en investigación anterior. Se acepta la participación en un ensayo observacional. 21.Tener otra neoplasia maligna conocida de otro tipo, excepto carcinoma localizado sometido a conización quirúrgica y tratado adecuadamente (consultar detalles en el protocolo) 22.Diagnóstico de trastorno de inmunodeficiencia primaria o adquirida o estar recibiendo cualquier otra forma de tratamiento inmunodepresor en los 7 días anteriores a la primera dosis del medicamento del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• AEs and serious adverse events (SAEs) (graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) and their causality in relation to BI-1607 or to the combination with trastuzumab
• Occurrence of DLTs. |
Acontecimientos adversos (AA) y acontecimientos adversos graves (AAG) (clasificados conforme a los Criterios terminológicos comunes para acontecimientos adversos [CTCAE] v. 5.0 y su causalidad en relación con BI-1607 o la combinación con trastuzumab.
Aparición de TLD. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study |
| A lo largo del estudio |
|
| E.5.2 | Secondary end point(s) |
• PK parameters for BI-1607 during the treatment period. The PK parameters will include area under the serum concentration-time curve (AUC), maximum concentration (Cmax), time to Cmax (tmax), and terminal half-life (t½)
• Anti-drug antibody response to BI-1607 in blood serum
• RO on circulating B lymphocytes.
• Best tumor response, objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, PFS, time to objective response, duration of objective response (DOR), and OS |
Parámetros FC para BI-1607 durante el periodo de tratamiento. Los parámetros FC incluirán el área bajo la curva de concentración sérica y tiempo, la concentración máxima, el tiempo hasta la concentración máxima y la semivida terminal.
Respuesta de anticuerpos antifármaco ante BI-1607 en suero sanguíneo.
OR en linfocitos B circulantes.
Mejor respuesta tumoral, tasa de respuesta objetiva (TRO) conforme a los Criterios de evaluación de la respuesta en tumores sólidos (Response Evaluation Criteria In Solid Tumors, RECIST) v. 1.1, supervivencia sin progresión (SSP), tiempo hasta la respuesta, duración de la respuesta (DdR) y SG |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study |
| A lo largo del estudio |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability |
| Tolerabilidad |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Escalada de dosis en la fase 1, cohortes de expansión en la fase 2a |
| Dose escalation in Phase 1, Expansion cohorts in Phase 2a |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Spain |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
